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Future Directions for Antiangiogenic Therapy in Lung Cancer

Insights From: Joachim G. Aerts, MD, PhD, Erasmus Medical Center Cancer Institute; Enriqueta Felip, MD, PhD, Vall d’Hebron University Hospital; Marina Garassino, MD, National Cancer Institute of Milan; Roy Herbst, MD, Yale School of Medicine
Published Online: Wednesday, Jan 11, 2017



Transcript:

Enriqueta Felip, MD, PhD:
I think there is a clear rationale to also analyze ramucirumab in the first line. In the first line, as we mentioned, bevacizumab is approved in combination with chemotherapy, but only in those patients with nonsquamous histology. There is an abstract presented at this ESMO 2016 analyzing the combination of carboplatin, paclitaxel, plus ramucirumab in first-line treatment. This is a phase II trial including 40 patients with non–small cell lung cancer. But an impressive 55% response rate on PFS longer than 5 months was supported in this phase II trial. So, yes, I think there is a clear rationale to analyze first-line treatment. We’ll have a drug that is approved in nonsquamous histology, but we don’t have any antiangiogenic drugs approved in lung cancer in patients, for example, with a squamous cell carcinoma histology.

Joachim G. Aerts, MD, PhD: Based on the results we saw in the second-line treatment with ramucirumab with an acceptable safety profile, one may expect that this is also true in the first-line setting. And this is also seen in the trial combining carboplatin and paclitaxel with ramucirumab, that the safety profile was quite what we expected. So, we saw again some hypertension and the trauma embolic events, but they were manageable and safe.

Roy S. Herbst, MD, PhD: I actually think in the frontline, the use of ramucirumab will most likely be in combination with immune therapies. I’ve been intrigued by the data we just recently presented at the ESMO 2016 meeting on behalf of a large team of investigators. We took ramucirumab and we put it with pembrolizumab. We call it the RAMBRO trial. And with that trial, really only being a phase I, it’s hard to make too much of it, but it showed that the combination could be used together safely. And it also showed that in lung cancer, we had 30% of patients responding. Now, we don’t know if they’d respond with pembrolizumab anyhow—probably not to the VEGFR2—to the ramucirumab, but many of the patients that responded were PD-L1–negative. So, I think there’s something interesting there, and we’re actually at Yale now seeking to do studies to look at the tumor microenvironment with biopsies, pre and post, to see what’s happening with the tumor in the microenvironment, to vessels, and to T cells.

Joachim G. Aerts, MD, PhD: With regard to the other VEGF inhibitors, there are now the tyrosine kinase inhibitors. We have now the large second-line study on nintedanib, comparing nintedanib/docetaxel to docetaxel alone. And this study showed the efficacy of the drug in the nonsquamous population. And besides that, there are a lot of other VEGF tyrosine kinase inhibitors in development. We have to see what comes up. We have to keep in mind that there have been a lot of patients treated already in the years before, and all these trials were negative. Not meaning that the drugs are not effective, but I think we have really to select in which patients we can or have to do these trials to optimize the efficacy of this treatment.

For me, one of the remarkable things is that I thought we knew already where this was heading to with the VEGF. And what we see now with all these new data coming up is that we see some signs, we see some effects of these kind of drugs that we didn’t know before. I think it’s really important that we look at these mechanisms and we try to optimize that to get the maximal activity of these drugs, and not use them as large blockbusters in large populations, but really select for novel combinations based on scientific knowledge.

Roy S. Herbst, MD, PhD: I guess it would be nice to see more studies of the VEGFR2 or the ramucirumab in the frontline setting with different chemotherapy combinations. Based on some of the preliminary data that our group and others presented at ESMO—looking at pembrolizumab, the PD-1 inhibitor, plus ramucirumab phase I trial—I’d love to see trials in the PD-L1–high group as defined by the 22C3 antibody of pembrolizumab/ramucirumab. And I would hypothesize that that combination might be better than pembrolizumab alone and also look at the angiogenesis inhibitor plus pembrolizumab maybe in the lower-expressing group. There, it would have to be compared to chemotherapy, which is still the standard of care. But I think there’s a lot of opportunity to use these agents selectively because if you think you want to upset the tumor microenvironment so that there are fewer T regulatory cells, allow the tumors to be more affected by immune checkpoint inhibitors; ramucirumab and other VEGF agents might have a role there.

Enriqueta Felip, MD, PhD: We are here to discuss antiangiogenesis. As we mentioned, antiangiogenesis is an important hallmark of cancer. We have now a number of drugs inhibiting this process, and this is what I want for the patient. We are at ESMO 2016. And during this ESMO meeting, very exciting studies analyzing immunotherapy, anti-PD-1 strategies, and anti–PD-L1 strategies will be presented here. So, we are discussing non–small cell lung cancer. We have improvements in this disease, but we need more strategies to really treat these patients with cancer. We’ll have the combination of antiangiogenic agents plus immunotherapy. We believe that the possibilities for our patients are increasing, and we will have more results in the next meetings.

Transcript Edited for Clarity
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Transcript:

Enriqueta Felip, MD, PhD:
I think there is a clear rationale to also analyze ramucirumab in the first line. In the first line, as we mentioned, bevacizumab is approved in combination with chemotherapy, but only in those patients with nonsquamous histology. There is an abstract presented at this ESMO 2016 analyzing the combination of carboplatin, paclitaxel, plus ramucirumab in first-line treatment. This is a phase II trial including 40 patients with non–small cell lung cancer. But an impressive 55% response rate on PFS longer than 5 months was supported in this phase II trial. So, yes, I think there is a clear rationale to analyze first-line treatment. We’ll have a drug that is approved in nonsquamous histology, but we don’t have any antiangiogenic drugs approved in lung cancer in patients, for example, with a squamous cell carcinoma histology.

Joachim G. Aerts, MD, PhD: Based on the results we saw in the second-line treatment with ramucirumab with an acceptable safety profile, one may expect that this is also true in the first-line setting. And this is also seen in the trial combining carboplatin and paclitaxel with ramucirumab, that the safety profile was quite what we expected. So, we saw again some hypertension and the trauma embolic events, but they were manageable and safe.

Roy S. Herbst, MD, PhD: I actually think in the frontline, the use of ramucirumab will most likely be in combination with immune therapies. I’ve been intrigued by the data we just recently presented at the ESMO 2016 meeting on behalf of a large team of investigators. We took ramucirumab and we put it with pembrolizumab. We call it the RAMBRO trial. And with that trial, really only being a phase I, it’s hard to make too much of it, but it showed that the combination could be used together safely. And it also showed that in lung cancer, we had 30% of patients responding. Now, we don’t know if they’d respond with pembrolizumab anyhow—probably not to the VEGFR2—to the ramucirumab, but many of the patients that responded were PD-L1–negative. So, I think there’s something interesting there, and we’re actually at Yale now seeking to do studies to look at the tumor microenvironment with biopsies, pre and post, to see what’s happening with the tumor in the microenvironment, to vessels, and to T cells.

Joachim G. Aerts, MD, PhD: With regard to the other VEGF inhibitors, there are now the tyrosine kinase inhibitors. We have now the large second-line study on nintedanib, comparing nintedanib/docetaxel to docetaxel alone. And this study showed the efficacy of the drug in the nonsquamous population. And besides that, there are a lot of other VEGF tyrosine kinase inhibitors in development. We have to see what comes up. We have to keep in mind that there have been a lot of patients treated already in the years before, and all these trials were negative. Not meaning that the drugs are not effective, but I think we have really to select in which patients we can or have to do these trials to optimize the efficacy of this treatment.

For me, one of the remarkable things is that I thought we knew already where this was heading to with the VEGF. And what we see now with all these new data coming up is that we see some signs, we see some effects of these kind of drugs that we didn’t know before. I think it’s really important that we look at these mechanisms and we try to optimize that to get the maximal activity of these drugs, and not use them as large blockbusters in large populations, but really select for novel combinations based on scientific knowledge.

Roy S. Herbst, MD, PhD: I guess it would be nice to see more studies of the VEGFR2 or the ramucirumab in the frontline setting with different chemotherapy combinations. Based on some of the preliminary data that our group and others presented at ESMO—looking at pembrolizumab, the PD-1 inhibitor, plus ramucirumab phase I trial—I’d love to see trials in the PD-L1–high group as defined by the 22C3 antibody of pembrolizumab/ramucirumab. And I would hypothesize that that combination might be better than pembrolizumab alone and also look at the angiogenesis inhibitor plus pembrolizumab maybe in the lower-expressing group. There, it would have to be compared to chemotherapy, which is still the standard of care. But I think there’s a lot of opportunity to use these agents selectively because if you think you want to upset the tumor microenvironment so that there are fewer T regulatory cells, allow the tumors to be more affected by immune checkpoint inhibitors; ramucirumab and other VEGF agents might have a role there.

Enriqueta Felip, MD, PhD: We are here to discuss antiangiogenesis. As we mentioned, antiangiogenesis is an important hallmark of cancer. We have now a number of drugs inhibiting this process, and this is what I want for the patient. We are at ESMO 2016. And during this ESMO meeting, very exciting studies analyzing immunotherapy, anti-PD-1 strategies, and anti–PD-L1 strategies will be presented here. So, we are discussing non–small cell lung cancer. We have improvements in this disease, but we need more strategies to really treat these patients with cancer. We’ll have the combination of antiangiogenic agents plus immunotherapy. We believe that the possibilities for our patients are increasing, and we will have more results in the next meetings.

Transcript Edited for Clarity
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